chr10-102615306-C-G

Position:

• chr10-102615306-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The ENST00000369902.8(SUFU):​c.1061C>G​(p.Ala354Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A354T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SUFU ENST00000369902.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.57

Genes affected

SUFU (HGNC:16466): (SUFU negative regulator of hedgehog signaling) The Hedgehog signaling pathway plays an important role in early human development. The pathway is a signaling cascade that plays a role in pattern formation and cellular proliferation during development. This gene encodes a negative regulator of the hedgehog signaling pathway. Defects in this gene are a cause of medulloblastoma. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SUFU. . Gene score misZ 1.9341 (greater than the threshold 3.09). Trascript score misZ 3.1202 (greater than threshold 3.09). GenCC has associacion of gene with apraxia, ciliopathy, ocular motor apraxia, Cogan type, nevoid basal cell carcinoma syndrome, Joubert syndrome, Joubert syndrome 32, medulloblastoma.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26607755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUFU	NM_016169.4	c.1061C>G	p.Ala354Gly	missense_variant	9/12	ENST00000369902.8	NP_057253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUFU	ENST00000369902.8	c.1061C>G	p.Ala354Gly	missense_variant	9/12	1	NM_016169.4	ENSP00000358918	P1
SUFU	ENST00000423559.2	c.1061C>G	p.Ala354Gly	missense_variant	9/10	1		ENSP00000411597
SUFU	ENST00000369899.6	c.1061C>G	p.Ala354Gly	missense_variant	9/11	1		ENSP00000358915

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jan 02, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 19, 2022	The p.A354G variant (also known as c.1061C>G), located in coding exon 9 of the SUFU gene, results from a C to G substitution at nucleotide position 1061. The alanine at codon 354 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Gorlin syndrome;C0025149:Medulloblastoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 30, 2018

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SUFU-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glycine at codon 354 of the SUFU protein (p.Ala354Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	0.022
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.29	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.37	T;T;T
Polyphen		0.016	B;B;B
Vest4		0.46
MutPred		0.59		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.58
MPC		0.62
ClinPred		0.83	D
GERP RS		5.3
Varity_R		0.11
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554854572; hg19: chr10-104375063;